For B Pharm & M pharm students

1. Chapter 02
Introduction to Controlled Drug
Delivery
By
Mr.prashant Jorapur M.pharM
LeCturer
Dept. of pharMa teChnoLogy
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

2. Classical drug delivery
For most of the pharmaceutical industries existence, drug
delivery induced simple, fast-acting responses via oral or
injection delivery routes
Problems associated with this approach
1. Reduced potencies because of partial degradation
2. Toxic levels of administration
3. Increase costs associated with excess dosing
4. Compliance issue due to administration pain
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

3. Why control drug delivery?
Goal of more sophisticated drug delivery
techniques
1.Deploy to a target site to limit side effects
2.Shepard drugs through specific areas of the
body without degradation
3.Maintain a therapeutic drug level for
prolonged periods of time
4.Predictable controllable release rates
5.Reduce dosing frequent and increase patient
compliance
Toxicity level
Injection
Controlled release
Therapeutic Level
Time
As the cost and complexity of individual drug molecules has
risen the problems with the classical delivery strategies over
took their benefits.
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

4. History of Controlled Drug Delivery
• Wurster technique 1949
• Coacervation (liquid encapsulation) 1953
• Mircroencapsulation 1960’s
– 65% of all current drugs use some form of micro-encapsulation
• Implants 1970’s
• Transdermal 1980’s
• Site directed systems 1990’s
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

5. Entrapment or Encapsulation
• During the 1970, scientists first began to encapsulate and
entrap drugs within polymers
• Encapsulation involves surrounding drug molecules with
a solid polymer shell
• Entrapment involves the suspension of drug molecules
within a polymer matrix.
drugpolymer
Drug
Polymer
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

6. Drug release by diffusion
• Early encapsulation and entrapment systems released
the drug from within the polymer via molecular
diffusion
– When the polymer absorbs water it swells in size
– Swelling created voids throughout the interior polymer
– Smaller molecule drugs can escape via the voids at a known
rate controlled by molecular diffusion (a function of
temperature and drug size)
Add
water
Add
time
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

7. Drug release by erosion
• Modern delivery systems employ biodegradable
polymers
– When the polymer is exposed to water hydrolysis occurs
– Hydrolysis degrades the large polymers into smaller
biocompatible compounds
– Bulk erosion process – Surface erosion process
mermer
Polymer
mermer mermer mermer mermer mermer mermer mermer mermer
Water attacks bond
mermer mermer mermer mermer mermer mermer mermer mermer mermer
mermer mermer mermer mermer mermer mermer mermer mermer mermer
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

8. Bulk erosion
(e.g. poly lactide, polyglycolic acid)
– When the polymer is exposed to water hydrolysis occurs
– Hydrolysis degrades the large polymers into smaller
biocompatible compounds
– These small compound diffuse out of the matrix through the
voids caused by swelling
– Loss of the small compounds accelerates the formation of
voids thus the exit of drug molecules
Add
water
Add
time
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

9. Surface erosion
(e.g., polyanhydrides)
–When the polymer is exposed to water hydrolysis occurs
–Hydrolysis degrades the large polymers into smaller
biocompatible compounds
–These small compound diffuse from the interface of the
polymer
–Loss of the small compounds reveals drug trapped
within
–Note these polymer do not swell.
Add
water
Add
time
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

10. How is entrapment or encapsulation
obtained?
The physical entrapment and encapsulation of drugs
within a polymer is complete via one of five
techniques
1. Wurster
2. Coacervation
3. Spray drying (or precipitation)
4. Coextrustion
5. Self-assembly methods
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

11. Wurster processing (1949)
• The Wurstur process is essentially a coating process
applied after a drug core is formed.
• The polymer shell is applied via spraying while the drug
cores (liquid or solid) is suspended and recirculated in a
gas stream
Gas
Drug
Polymer
Gas
Drug
Polymer
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

12. Coacervation Technique
• STEP #1:
– Polymer dissolved in a solvent (or oil)
– Drug dissolved in water
• STEP #2:
– 2 liquids are rapidly mixed
– water droplets form within the solvent
• STEP # 3:
– Emulsion from step #2 is mixed rapidly with
fresh water
– Oil droplets within the fresh water phase
– Oil droplets contain original dispersed
water/drug phase
– Oil diffuses into the fresh water phase
precipitating the polymer & entrapping the drug
Drug/H20
Polymer/Oil
H20
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

13. Supercritical fluid precipitationSolvent-polymer
solution from
pump
CO2
from
pump Heat exchanger
Flow straightener
Nozzle
Nozzle
contraction
Precipitate
0.2µm
filter
Back pressure
regulator
Gas outlet
Poly(l-lactide) ~1-µm diameter
particles formed by PCA processingB.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

14. Co-extrusion processing
• These concentric
cylinders then breakup
into individual packets
either driven by air
flow, electrostatic or
mechanical vibration
Syringe pump
HV
supply
Neg.
Drug
Polymer
• There are numerous co-extrusion processes but they all
share one feature – the polymer shell is flowed
concentrically around a pipe containing the drug
formulation
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

15. Self-assembling delivery systems
The next advance was to construct materials/polymers
that would self assemble with drugs to create
controlled drug delivery vehicles
• Self assembly is typically approach via one of two
methods:
1. Using a molecule that has a hydrophilic head
and hydrophobic tail to form a shell, or
2. Electrostatic interaction to entrap drug
molecules
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

16. Micelles & Bilayers
• Entrapment by micelle or bilayer
formation can be obtained using
lipids, surfactants and block
copolymers
Polar Head
Group
(hydrophilic)
Fatty Tail
(hydrophobic)
Bilayer
monlayer
micelle
Lipid entrapment
or liposomes are
the most common
•Small unilamellar
(10 to 50nm)
•Large unilamellar
(50nm to 1um)
•Large multilamellar
(100nm to 20mm)
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

17. Liposome Formation
• Liposome are typically formed by:
– Fissure homogenization
– High pressure homogenization
– Extrusion through polycarbonate membranes
• Large multilamellar liposomes are prepared by hydration of a dry
lipid film by an aqueous solution.
– Thickness of the film, temperature, lipid composition effect lipid size
• Large unilamellar liposomes are prepared by vigorous agitation
(fissure or high pressure) during the hydration process
– Mixing strength, lipid and surfactant control lipid size
• Small unilamellar liposomes are typically prepared by taking
LUV suspensions and passing them through fine matrix
polycarbonate membrane.
– Membrane pore size largely controls the resulting SML size
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

18. Electrostatic entrapment
• Ionic attraction between dissimilar charged molecules
can be used to attach a molecule to the drug
• The resulting complex may provide protection by
containing the drug molecule on the interior or
simply inactive the drug Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3
HO
NH
CH3
OH
Cl
HO NH
CH3
OH
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3
HO
NH
CH3
OH
Cl
HO NH
CH3
OH
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3
HO
NH
CH3
OH
Cl
HO NH
CH3
OH
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complexl -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Na
Dodecyl Sodium Sulfate
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Na
Dodecyl Sodium Sulfate
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Na
Dodecyl Sodium Sulfate
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3 B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

19. Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3
Aqueous PhaseAqueous Phase
Organic PhaseOrganic Phase
HO
NH
CH3
OH
Cl Na
Dodecyl Sodium Sulfate
HO NH
CH3
OH
Na Cl
l-PhenylephrineHydrochloride
l -Phenylephrine-DodecylSulfate Complexl -Phenylephrine-DodecylSulfate Complex
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3
[CH2]11
CH3 OSO3[CH2]11
CH3 OSO3
Dissolution Mechanism
N
NH2
CH2CH3 OSO3
11
N a C l
Na Cl
Na C l
N
NH2
Cl
Na
CH2CH3 OSO3
11
Solid Tacrine-Surfactant (T•S)s
Dissolved Tacrine-Surfactant (T•S)aq
Free Tacrine (T•Cl)aq
and Surfactant (Na•S)
s(T S)× aq(T S)×
k1
aq(T S) NaCl× + aq(T Cl) (Na S)× + ×
k2
Phase Change Reverse Ion Pairing Process
• Complexes are prepared
by vigorously mixing
aqueous solutions of the
surfactant and drug.
• The complex either
precipitates as a solid or
can be separated by
partitioning to an
organic
• Unpairing
happens
naturally in the
presents of salts
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

20. More than protection and release:
targeting a site
• The coating or matrix surrounding the
therapeutic molecule can also be used to direct
the particle to a targeted site.
• Such systems include:
1. Liposomes
2. Surfactant
3. Nanoparticles
4. Antibodies, enzymes and other proteins
5. Viral vectors
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

21. Liposomal enhanced targeting
• Liposomes have demonstrated the tendency to collect
in a specific tissue
– There is some evidence that liposomes gather in the tissue
of tumors
• Lipisomes can take the form of positively charged,
negatively charged and neutral – charge can help
direct particles to specific oppositely charged
locations
• Liposomes largely consist of Lecithin and cholesterol,
naturally occurring substances in the body, therefore
well tolerated and have some naturally occurring
collection sites B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

22. Surfactants enhanced targeting
• Increase absorption into cell membrane
– Acting as a wetting agent surfactants, increases the contact
area between the drug and cell wall, facilitating the
absorption of molecules into the cell membrane
• Increase solubility of drug into carrier
– Introduction of a surfactant into a solvent lowers the surface
tension thereby increasing solubility limits
• Increase stability of vehicle
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

23. Nanoparticles enhanced targeting
• Particle sizes ranging from 10nm to 1µm
• Particle size alone can significantly effect
biodistribution
– Particles less than 10 nm are 400 time more likely to cross
the intestinal wall than 1 micron pariticles
– Particles between 1 and 10 micron deposit in the deep lung
via impaction while other escape during breath or deposit in
the mouth
– Particles below 500 nm can escape the filtering of the liver
and kidney for several cycles
• Nanoparticles are highly charged coupled with high
surface to volume ratio -- this property can effect
cellular interactionB.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

24. Antibody enhanced delivery
• The attachment of antibodies to delivery vehicles can
be used to increase tissue sensitivity
• Attachment occurs by physical absorption or covalent
bonding
• Monoclonal antibodies can be directed against a
single determinant – similar to a lock and a key.
Tissue
Antibody
Antibody
Antibody
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

25. Viral vectors
• Viruses have evolved a way of
encapsulating and delivering genes
to human cells in a pathogenic
manner.
• Scientist are attempting to take
advantage of natures delivery
system.
• Viruses would be genetically altered
to carry the desired normal gene and
turn off the natural occurring disease
within the virus.
[Video from www.biosciednet.org/portal]
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

26. Viral vectors
Candidate viruses
– Retroviruses [e.g., HIV]
• RNA virus that infect humans
• Ability to target genes
• Dividing cells only
• Risk of mutagenesis
• 8kb
– Adenoviruses [e.g., virus that causes common cold]
• Not highly pathogenic
• Do not integrate into the genome
• Can be aerosolized
• Transient gene expression
• 8-10kb
– Adeno-associated virus [inserts only at chromosome 19]
– Herpes simplex virus [e.g., virus that causes cold sores]
• Viral vectors will only be effective a few times before the
body becomes resistant!
[Image from McKee & McKee, Biochemistry an Introduction]
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

27. Other delivery vehicles
Up to this point I have concentrated on particle
delivery vehicles, but several other have
evolved in recent history
1. Hydrogels
2. Transdermal patches
3. Implantable pumps
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

28. Hydrogels
(e.g. polyacrylic acids)
• Cross-linked, hydrophilic, 3-D polymer networks that
are highly permeable
• Do not swell in the presence of water unless activated
• Swelling activate by pH, temperature, electric field
• Drug release happens via void generated & diffusion
(diffusion rate is regulated by cross-linking ratio)
mermer mermer mermer mermer
mermer mermer mermer mermer
Add water
+
activator
mermer mermer mermer mermer
mermer mermer mermer mermerB.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

29. Implantable pumps
The pumps usually use polymer swelling to drive
drug formulations out of a reservoir
Polymer Drug/H20
Drug/H20
Water
Drug/H20
Water
Swell
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR

30. Transdermal patches
• Topical skin application
• 3 layer design
– adhesive
– polymer/drug matrix
– water proof backing
• Drug is delivery to the skin up to saturation
• Blood via circulation removes drug locally and more
escapes the matrix to return levels to saturation
Skin
B.L.D.E.A'S SSM COLLEGE OF
PHARMACY & RC , VIJAYPUR